Despite impressive progress in understanding the molecular, cellular and circuit-level correlates of major depression, the biological mechanisms that causally underlie this disease are still unclear, hindering the development of effective preventive and therapeutic procedures. One possible reason for this situation is that almost all research in this area focuses on the involvement of abnormalities in neuronal functioning, whereas the involvement of non-neuronal brain cells was not thoroughly examined. Over the last decade it has been suggested that glia cells, particularly astrocytes, may be also involved in the pathophysiology of depression, however, almost no research has focused on the role of microglia in this disease.
Microglia, which comprise about 15% of brain cells, serve as the representatives of the immune system in the brain, and therefore their activation plays a major role in brain infection, injury, and neurodegenerative diseases. In addition, they are highly motile in their resting/quiescent state, and actively participate in synaptic changes, micro-damage repair, and neurogenesis.
Microglial activation and brain inflammatory cytokines have been implicated in the responsiveness to stress, which both in humans and in animal models has been implicated as a major trigger for depression. Specifically, exposure to acute stressful conditions can directly induce hippocampal microglial activation, and the microglial inhibitor minocycline was reported to block stress-induced hypothalamic IL-1 secretion. Furthermore, exposure to repeated restraint or social disruption stress for 4-14 days induced microglia proliferation and activation in several stress-responsive brain regions. In addition, the depressive and neurogenesis suppressive effects of chronic stress in rodents were found to be mediated by the microglial-derived cytokine interleukin-1. Together, these findings suggest that stress-induced microglial activation is critically involved in the development of depression and neurogenesis suppression. As such, the main hypothesis for treating stress and mood disorders proposes inhibiting microglial activation (e.g., Steiner et al., 2011, Journal of Neuroinflammation, 8:94).
Nevertheless, the art does not describe or suggest that following the initial phase of microglial proliferation and activation there is a subsequent phase of microglia apoptosis, dystrophy and decline, which contradictory to the art, should be treated by microglia stimulation.
There is an unmet need for improved compositions and methods for treating and/or ameliorating mood and stress related disorders.